Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic...

Area of Science:

• Genetics
• Oncology
• Epidemiology

Background:

• Breast cancer (BC) risk is influenced by both rare pathogenic variants (PVs) in high-penetrance genes and common genetic variants.
• Accurate risk stratification is crucial for effective BC screening and prevention strategies.

Purpose of the Study:

• To assess the combined impact of PVs in BC predisposition genes and polygenic risk scores (PRS) on BC risk in the general population.
• To evaluate the utility of PRS in refining BC risk estimates for individuals with and without PVs.

Main Methods:

• Evaluated PVs in 9 key BC genes (BRCA1, BRCA2, ATM, CHEK2, PALB2, etc.) in over 50,000 BC cases and controls.
• Developed and assessed BC-specific PRS using genome-wide association study data.
• Estimated BC odds using penalized logistic regression, integrating PV status, PRS, and family history.

Main Results:

• PRS significantly modified lifetime BC risk across percentiles for both noncarriers and carriers of PVs.
• Over 95% of BRCA1, BRCA2, and PALB2 carriers had >20% lifetime BC risk, further stratified by PRS.
• PRS identified a substantial proportion of ATM and CHEK2 carriers with elevated lifetime BC risk (>20%).

Conclusions:

• Polygenic risk scores enhance the personalization of BC risk assessment for carriers of pathogenic variants in predisposition genes.
• Integrating PRS into risk models can help identify individuals needing closer monitoring and tailor screening strategies, potentially preventing over-management.